A futility study showed in several analyses that both doses of the drug that were tested (15 mg and 45 mg) were futile at slowing disease progression, Tanya Simuni, MD, of Northwestern University, and colleagues reported online in the Lancet Neurology.

"Our results show that pioglitazone is unlikely to be efficacious as a disease-modifying intervention in early Parkinson's and therefore is not recommended for further testing for that indication," they wrote. "Although our negative results are disappointing, the design of this futility study is an example of a useful and efficient study design that can exclude a compound unlikely to be successful in larger and more costly phase III studies."

Some work, particularly in animal models, had suggested that thiazolidinediones (TZDs) like pioglitazone might have neuroprotective effects in neurodegenerative diseases, and, in particular, pioglitazone may slow progression of Parkinson's. The mechanism was thought to be the ability of TZDs -- which are peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists -- to inhibit activation of microglia and astrocytes as well as the production of pro-inflammatory cytokines and nitric oxide.

This class of agents -- including troglitazone (Resulin), rosiglitazone (Avandia), and pioglitazone (Actos) -- had come under fire as diabetes treatments for ties to liver toxicity, heart disease, and bladder cancer, respectively. Troglitazone was pulled from the market in 2000, and the other two drugs remain on the market under FDA's risk evaluation and mitigation strategy (REMS) program.

The investigators conducted their phase II futility study in 210 patients who had a diagnosis of early Parkinson's and were taking either rasagiline or selegiline. These patients were randomized to one of two doses of pioglitazone (15 mg/day or 45 mg/day) or to placebo.

The primary outcome was the change in the total Unified Parkinson's Disease Rating Scale (UPRDS) score after 44 weeks.

In the main analysis, the difference between the 45-mg dose and placebo was futile, but the difference between the 15-mg group and placebo wasn't.

In planned sensitivity analyses, the 15-mg dose was also found to be futile -- but the 45-mg dose wasn't. The investigators explained that the sensitivity analyses of the primary outcomes used "the last value carried forward (LVCF) to handle missing data and using the completers' only sample."

Finally, in a post-hoc repeated measures mixed model analysis, both doses proved futile, leading the researchers to conclude that pioglitazone has no role in Parkinson's treatment.

"Unfortunately, this is another study in which animal models were not predictive of efficacy in human beings," they wrote. "A possible explanation for negative outcomes is that toxin animal models are not reflective of Parkinson's disease pathogenesis. Another possibility is that pioglitazone failed to reach the target nigral neurons and achieve sufficient drug exposure in this study."

None of the adverse events -- six in the 15-mg group, nine in the 45-mg group, and three in the placebo group -- were determined to be related to the drug or placebo, the researchers said.

They wrote that attention in Parkinson's research has switched to the "discovery and validation of biomarkers of disease progression, which we hope will accelerate the development of disease-modifying or curative agents."

In an accompanying editorial, Fabrizio Stocchi, MD, of Institute for Research and Medical Care in San Raffaele in Italy, said the results "represent another disappointment in this difficult field."

He agreed that the animal model in which the initial associations were made may be problematic since those models rely on administering toxins that may not provoke the same pathogenic processes as Parkinson's. Nor do animal models always "recapitulate the progressive features of sporadic Parkinson's, and the administration of the study drug is not always started after neurodegeneration is induced," he wrote.

Stocchi added that the sensitivity of UPDRS is good, but it may not be as good in patients with early or mild disease: "A biomarker that could be used to confirm diagnosis or as an endpoint to measure disease progression and drug efficacy could solve the problems of sensitivity and subjectivity," he added.

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